DE1948507C2 - 4- (2-Hydroxy-3-aminopropoxy) indole derivatives, their salts, processes for their preparation and medicines - Google Patents

Description

0-CH ₂ -CH-CH ₂ -NHR ₁

! 0

R, for an alkyl group with 3 to 5 carbon atoms stands and

R _{2 is} a group CH ₂ OH or COOR ' ₂ , in which R' _{2 is} a lower alkyl group,

and their salts with pharmaceutically acceptable acids.

2. Process for making the compounds

according to claim 1, characterized in that either in a known manner

a) from compounds of the general formula VII,

OH CH ₂

0-CH ₂ -CH-CH ₂ -N -R ₁

0-CH ₂ - CH CH ₂

(Ha)

wherein R _{2 has the} above meaning, or compounds of the general formula Hb,

CH ₂ - CH-CH ₂ Y

(Db)

wherein R, has the above meaning, reacts or c) for the preparation of the compounds of the general Formula Ia,

OH

0-CH ₂ -CH-CH ₂ -NH-R ₁

CH ₂ OH

wherein R _{1 has the} above meaning, compounds of the general formula Ib

OH

0-CH ₂ -CH-CH ₂ -NH-R ₁

30th

If)

COOR ₂

(VI)

in which R _{1 and R 2 have the} above meanings, splitting off the benzyl group hydrogenolytically or b) compounds of the general formula Ha

45

in which R _t and R ' _{2 have the} above meanings, and the compounds of general formula 1 thus obtained are optionally converted into their salts with pharmaceutically acceptable acids.

3. Medicinal products, characterized in that they contain compounds of general formula I or their physiologically acceptable salts together with the pharmaceutically customary auxiliaries and carriers contain.

The invention relates to the subject matter of the claims.

Particularly interesting compounds of the general formula I are those in which Ri is the isopropyl, sec-butyl, tert-butyl, tert-pentyl, 3-pentyl group, in particular represents the tert-butyl group.

The processes can be carried out analogously to known methods.

Method a) is a debenzylation. It takes place z. B. by hydrogenation in the presence of a catalyst, preferably a palladium catalyst. One works in an inert under the reaction conditions Solvents, e.g. B. in ethyl acetate or in a lower alkanol such as ethanol. Implementation is preferred carried out at normal temperature and normal pressure. After the hydrogenation has ended, the The catalyst is removed and the filtrate is evaporated to dryness. Process b) can be carried out analogously to for the production known 3-amino-2-hydroxypropoxyaryl compounds

can be carried out under known conditions. It is preferably done in one under the reaction conditions inert organic solvents, e.g. B. in a cyclic ether such as dioxane or in one aromatic hydrocarbon such as benzene or toluene. The reaction temperature can be between 20 and 120 ° lie; reflux is preferably carried out at the boiling point. The addition of an acid-binding agent By means of e.g. B. an inorganic base, e.g. B. an alkali metal carbonate such as potassium carbonate, or one organic base, such as pyridine and triethylamine, or a second mole of the compound of the general Formula III can be beneficial, but is not necessary. Y in the general formula is Hb Fluorine, chlorine, bromine or iodine, preferably chlorine or bromine.

After the reaction has ended, the reaction mixture can be worked up by evaporating it, the residue between aqueous acid, e.g. B. 1 N tartaric acid or 1 N hydrochloric acid, and one with it immiscible organic solvents that are inert under the prevailing conditions, such as ethyl acetate, shakes out, the acidic aqueous phase neutralized, for. B. with aqueous sodium carbonate solution, the released basic products in an organic solvent which is inert under the prevailing conditions, such as Methylene chloride, and finally the separated and dried organic phase is evaporated, preferably under reduced pressure.

Process c) is a reduction of a carboxylic acid ester to the primary alcohol. It is done with a complex aluminum hydride such as lithium aluminum hydride or sodium dihydro-bis (2-methoxy-ethoxy) -a! uminate. The reaction is carried out in an organic solvent which is inert under the reaction conditions, e.g. Am a cyclic or open-chain ether such as. B. tetrahydrofuran. The implementation is preferably carried out at the boiling point of the reaction mixture. The reaction mixture can, for. B. be processed, by adding water, filtering off the resulting precipitate and removing the organic phase separates. The precipitate is then inert with the same under the prevailing conditions Washed out organic solvent and dried the combined organic phases, for. B. over Sodium sulfate. When the organic phase is evaporated, the compounds of the general formula Ia remain as a residue.

The esters of the general formula Ib can, for. B. also according to Bouveault-Blanc, using sodium in alcohol be converted into the compounds of general formula Ia.

The starting compounds can be obtained analogously to known methods. The connections the general formula lla or Hb one obtains ζ. Β. by reacting the compounds of the general formula IV,

OH

(IV) epihalohydrin. Since epihalohydrin molecules have two reactive sites, a mixture of the compounds of the general formulas Ua and Hb is obtained, but when used in process b) they give the same end product. A separation of the mixture can therefore be dispensed with, although it can be carried out easily (e.g. chromatographically).
The compounds of the general formula IVa,

worm Ri above meaning besii / .t, as Sülz or in Presence of a rabbit, with the corresponding OH

(Wa)

I COORJ
H

in which R'2 has the above meaning, are sensitive to oxidation and are therefore preferably used in the absence of oxygen, for example in a Nitrogen atmosphere, further implemented.

The compounds of the general formula IVa are obtained, for. B. by debenzylating the compounds of general formula V,

O - CH

(V)

COORJ

wherein R'2 has the above meaning.

The 4-hydroxy-2-hydroxymethylindole is obtained, for. B. by reducing the compounds of general Formula V, and subsequent debenzylation of the 4-benzyloxy-2-hydroxymethylindole formed.

The compounds of general formula V can be, for. B. obtained by 2-benzyloxy-6-nitro-toluene in the presence of a suitable alkali metal catalyst with an oxalic acid ester of the general formula VI,

COORl
COOR ₂

(VI)

wherein R'2 has the above meaning, and the condensation product reductively, z. B. cyclized by means of sodium dithionite in a weakly alkaline medium or by adding a solution of the condensation product in glacial acetic acid to a boiling suspension of iron powder in a lower alkanol such as ethanol.
5 ^r> The compounds of general formula V may be obtained from a 4-benzyloxyindole-2-carboxylic acid chloride by esterification of 4-benzyloxyindole-2-carboxylic acid, respectively.

The compounds of the general formula VI are obtained, for. B. by implementing the compounds of general formulas Ha and Hb with the compounds of general formula VIII,

CH _; —NH-R ₁

where Ri has the above meaning.

(VIII)

The compounds of general formula 1 can be used in free form or in the form of addition salts with Acids are present. The compounds in free form can be converted into salts in a known manner, for example the Hydrochloride or hydrogen maleate, and vice versa.

Insofar as the production of the starting products is not described, these are known or per se known processes or analogous to those described here or analogous to those known per se Process can be produced.

The compounds of general formula I in free form or in the form of their physiologically tolerable ones Salts have interesting pharmacological properties. They can therefore be used as a remedy will:

a) Blocking effect on the adrenergic ^ receptors

The compounds of general formula I show on spontaneously beating, isolated guinea pig atria an antagonistic effect against the frequency-increasing and amplitude-increasing effect of adrenaline, this antagonistic effect occurring at bath concentrations from about 5 × 10 ~ ⁹ to IfJ- ⁶ g / ml. Table 1 shows that on

Table 1

spontaneous, isolated guinea pig vestibule an δ-blocking one that is similarly strong to propranolol Have activity (column A), but that the undesirable negative inotropic activity (column B) is relatively smaller than with propranolol and therefore the therapeutic range in this regard (A: B) is significantly higher than with propranolol:

jS-blocking activity in the spontaneously striking, isolated guinea pig atrium (method: HeIv. Physiol. Acta 25 CR 217 (1967)

link A. relative B. relative AWAY Example no. (Propranolol = 1) (Propranolol = 1) therapeutic jS adrenergic blocking activity 10 negative inotropic activity 2.8 broad (50% adrenaline inhibition = ED ₅₀ ) -4.3 (10% decrease in amplitude) **** 1 absolutely 4.3 absolutely -0.36 (Propranolol = 1) 1 (ηΐμΐηοΐ / ml) 5.9 (πΐμίηοΙ / ΓηΙ) 0.0062 3.6 2 0.013 7.0 0.32 0.012 ~ 4.3 3 -0.03 3.7 -0.9 0.016 -12 13th 0.03 4.6 ~ 2.5 0.012 955 16 0.022 0.56 145 0.013 580 18th 0.011 1 44 1 240 22nd 0.037 58 390 23 0.028 75 49 Propranolol 0.2 68 1 0.13 1.0

Compounds 45 produce 0.02 to 0.5 mg / kg i.v. on the anesthetized cat. v. sets in, lli

of the general formula I to a strong inhibition of the isoproterenol [1- (3,4-dihydroxyphenyl) -2-isopropyl-aminoethanol] caused tachycardia and lowering of blood pressure, the effect at doses of approx. From Table 2 it can be seen that the compounds are also significantly more active in the anesthetized cat with regard to the ^ -blocking effect than Propranolol:

Table 2

^ -blocking effect on the anesthetized cat (dose: 0.1 mg / kg i.v.)

link % Hem Iso-I % Hem Iso-Il dose Example no. mung of the (Blows / mung of the (mm Hg) Isoproterenol Isoprena min) Isoprena fcg / kg i. v.) lintachy- lin blood cardia pressure- lowering 1 80 + 33 68 -35 1.0 2 100 + 42 95 -36 0.5 3 100 + 30 89 -34 0.5 4th 96 + 48 89 -29 2.0 13th 92 + 33 99 -33 1.0

7th % Hem 19 48 507 Iso-Il 8th dose mung of the (mm Hg) Isoproterenol continuation Isoprena ^ g / kg IV) link lintachy- get % Hem Example no. kiirdie (Blows / mung of the min) Isoprena 100 lin blood -18 1.0 97 pressure- -39 0.5 82 lowering -37 0.5 16 44 + 24 100 -43 1.0 22nd + 30 100 32 + 24 95 Propranolol + 35 71

Iso-I: change in heart rate after isoproterenol administration. Iso-II: change in blood pressure after isoproterenol administration

method

The blood pressure and heart rate of cats under Uiethan Chloraiosis anesthesia are measured. While Increasing intravenous doses of isoproterenol are tested during a control period. This results in a dose that produces a maximum effect, d. H. the administration of even higher doses does not result in higher ones Effect with itself. A dose is then chosen that results in a submaximal increase in heart rate (22 up to 48 beats / min) and a submaximal decrease in blood pressure (29 to 43 mm Hg). This dose and their effects vary from one experiment to another, depending on the sensitivity of the animal (see Table 2). the Compound to be tested is then in the dose indicated in Table 2 (0.1 Hg / kg) over a Infused time span of 30 minutes. The dose of isoproterenol selected during the control period will be also injected during the infusion time and the effect on heart rate and blood pressure compared to the effect that was achieved during the control period. Compounds that the f? -Adrenoreceptors able to block, inhibit (reduce) the action of isoproterenol. The percentage Decreasing the effect of isoproterenol on heart rate and blood pressure provides a measure of the jS-adrenoreceptor-blocking effect of a sub-

25 punch.

The inhibitory effect of some compounds of the present application at a dose of 0.1 mg / kg is shown in Table 2. It can be seen from this that all compounds are significantly more active than

30 propranolol.

The compounds of the formula I accordingly have a blocking effect on the adrenergic j3 receptors and can therefore, inter alia. for the prophylaxis and therapy of coronary diseases, especially for Treatment of angina, use. Because of their antiarrhythmic effects, they are also suitable for the treatment of cardiac arrhythmias.

b) Metabolic effect

They also show interesting metabolic effects: they cause a significant inhibition of the in the plasma by isoproterenol stimulable lipolysis (fatty acid build-up) and glycogenolysis (plasma glucose increase).

Table 3 shows that the compounds in this indication are about 20-100 times more active than Propranolol.

Table 3 Metabolic effect on blood glucose and fatty acid increases in rats

link Example no.

Inhibition of isoproterenol-stimulated (ED ₅₀ , relative to propranolol) Glucose release

absolutely relative to

(mg / kg) propranolol

Glycerine release

absolutely relative to

(mg / kg) propranolol

4th 0.0245 (s. c.) 31 0.0135 (S. C.) 32 0.07 (p.o.) Propranolol 6.9 (P-O.) 1.1 (s- c.)

45 82 99

1 1 0.025 (sc)
0.032 (sc)
0.2 (po)

20th
0.6

24

19th

100

method

400 ng / kg s. C. Isoprolcrenol are used together with mil administered to the test substance. The concentralization of the Glycerol and glucose in the Blui comes with one Autoanalyzer according to the method of S. l.aurell et al .. HeIv. Chim. Aeta 13 (l% b) 317-322 determined. Under liDio is the dose of the test substance that inhibits glucose or glycerol release by isoprotein-stimulated by 50%.

Because of these metabolic effects, the Compounds of the general I ormel I in conditions which lead to an undesirable metabolism mobilization that occurs in the event of psychological stress will.

c) Acute toxicity

Information on the compatibility of the compounds of the formula I is illustrated in Table 4 apparent toxicity studies.

Table 4 Test animal LD ₅₀ (mg / kg) acute toxicity Mouse p.o. 1000 link Mouse p. O. 65 Example 13 Rat p.o. 34 Example 32 Rat i. v. 3.3 Mouse p.o. 600-800 *) Rat p. O. 920 Propranolol Rat i.v. 35

*) From BSM 4057 M.

From Table 4 it can be seen that the LD5n dose of the compound of Example 13 in The size range of the propranolol; the connection Example 32 is about 10-30 times more toxic than propranolol. Since the connections though are cardially as well as metabolically several times more active than the comparison substance, should be theirs Usability in pharmacy is beyond doubt: the compound of Example 13 shows the isolated Guinea pig atrium had 5.9 times higher j3-blocking activity and 955 times higher therapeutic activity Spread out as propranolol (Table 1) Hie connection of Example 32 is metabolically 99 or 100 times more active than propranolol (Table 3). If one calculates z. B. for the Example 32 compound the relationship

LD ₅₀ (rat, po)
ED ₅₀ (rat, glycerine)

LD ₅₀ (rat, po)

ED ₅₀ (rat, glucose)
this gives a quotient of

34, ",, __ 34

the corresponding values for propranolol are

920
6.9

= 133 or

920
20th

= 46:

0.07

= 487 or

0.2

170;

the safety margin is thus significantly greater than with propranolol.

In addition, the compatibility of the compounds of general formula I was based on studies on Dog determined:

a) The VerabiTir ¹ '1er compound of Example 3 in a f ^ <sis of 30 mg / kg / day po for 4 weeks led only to nictitating membrane prolapse and reddening of the skin.

100 mg / kg / day administered for 2 weeks caused severe skin reddening and one slight weight loss. No significant toxic effects were found post-mortem.

b) The administration of 30 and 100 mg / kg / day of the compound of Example 1 also showed one better tolerability than propranolol.

The compounds of the general formula I can therefore be administered as medicaments. The daily dose is about 10 mg to about 400 mg.

In the following examples showing the manufacture explain the compounds according to the invention in more detail, all temperatures are given in degrees Celsius and are uncorrected.

example 1

Ethyl 4- (2-hydroxy-3-isopropylaminopropoxy) indole-2-carboxylate (Method b)

A solution of 106 g of ethyl 4-hydroxy-indole-2-carboxylate in 200 ml of dioxane is mixed with a solution of 20 g of sodium hydroxide in 500 ml of water and at 120 g of epichlorohydrin were added to room temperature and the mixture was stirred at 80 ° for 3 hours. After cooling down extraction is carried out with a mixture of 2 liters of chloroform and 400 ml of dioxane, and the organic is washed Phase with saturated saline solution, dry it over sodium sulfate and evaporate it to dryness. The The dry residue is dissolved in 200 ml of dioxane, 190 ml of isopropylamine are added and the mixture is maintained during l hour at a temperature of 65 - 70 ° and evaporates to dryness again. The basic portion of the dry residue is separated off in the usual way and recrystallized from isopropanol. (M.p. 149-151 °).

The ethyl 4-hydroxy-indole-2-carboxylate used as the starting material is made, for example, as follows:

A mixture of 0.14 kg of potassium tert-butoxide, 1.2 kg of diethyl oxalate and 243 g of 2-benzyloxy-6-nitrotoluene is heated to 60 ° for 2 hours, the butanol and ethanol are distilled off in vacuo, the residue shaken between dilute acetic acid and toluene, the toluene solution with a mixture of 110 ml 20% sodium carbonate solution and 550 ml of saturated sodium chloride solution neutralized and the washed in this way Toluene solution evaporated to dryness. The solution of the dry residue in glacial acetic acid is now slowly added dropwise in a boiling suspension of 900 g of iron powder in ethanol and keeps the mixture for 1 hour Reflux. The cooled solution is carefully made alkaline by means of a soda solution and afterwards Addition of standard super oil, suctioned off using Hyflo, it is washed with water and the filter residue is stirred at room temperature with chloroform, sucks again

over Hyflo and washed with chloroform. The chloroform solution is washed with water and then evaporated. The 4-benzyloxyindole-2-carboxylic acid ethyl ester remaining as residue is recrystallized from trichlorethylene. Sinp. 168-170 °. From this, 4-hydroxyindole-2-carboxylic acid ethyl ester is obtained by catalytic debenzylation with palladium / hydrogen. (M.p. 159-160 ° (from water)).

Example 2

4- (2-Hydroxy-3-isopropylaminopropoxy) indole-2-carboxylic acid methyl ester (Method a)

9.5 g of 4-hydroxy-indole-2-carboxylic acid methyl ester, 46 g of epichlorohydrin and 2 drops of piperidine are 4 Heated to the boil for hours. The excess epichlorohydrin is distilled off under reduced pressure and the residue was taken up in 15.65 g of N-benzylisopropylamine and 50 ml of dioxane and taken for 2½ hours heated to boiling. It is evaporated to dryness, the residue is triturated several times with petroleum ether (for Removal of excess N-benzylisopropylamine) and then crystallizes 4- [3- (N-Benzylisopropylamino) -2-hydroxypropoxy] -indole-2-carboxylic acid methyl ester from ethanol / ethyl acetate, 115-117 °.

16.8 g of the above benzyl compound are dissolved in 200 ml of methanol and in the presence of 5 g Palladium catalyst (5% palladium on aluminum oxide) with hydrogen until the end of the Shaken hydrogen intake. The catalyst is filtered off and evaporated under reduced pressure Dry and then shake out the residue between ethyl acetate and 1 N tartaric acid solution.

The combined tartaric extracts become carefully alkaline with 10% soda solution while cooling with ice and then extracted with methylene chloride. The residue from evaporation over magnesium sulfate dried methylene chloride phases are crystallized from ethyl acetate. The compound named in the title crystallizes in needles with a melting point of 143-145 ° (N-cyclohexylsulfamate needles from ethanol / ether. 110-113 °).

4-Hydroxy-indole-2-carboxylic acid methyl ester (melting point 202-203 °, needles from methanol) are obtained by Debenzylation of 4-benzyloxyindole-2-carboxylic acid methyl ester (m.p. 193-195 °, from ether) and the latter Compound of 4-benzyloxyindole-2-carboxylic acid by esterification with diazomethane in methanolic-acetone Solution.

Example 3

Ethyl 4- (3-tert-butylamino-2-hydroxypropoxy) indole-2-carboxylate (Method a)

The procedure is analogous to that given for Example 2, except that 1. methyl 4-hydroxyindole-2-carboxylate is used the ethyl 4-hydroxyindole-2-carboxylate and 2. instead of N-benzylisopropylamine the N-benzyl-tert-butylamine is used

The ethyl 4- [3- (N-benzyl-tert-butylamino) -2-hydroxypropoxy] -indole-2-carboxylate crystallizes as the hydrochloride from ethanol (melting point 227 °, decomp.). By debenzylation as in Example 2, the im Compound named in the title, the N-cyclohexylsulfamate of which from ethanol / ether in needles with a melting point of 169-171 ° crystallized

Example 4

Ethyl 4- (2-hydroxy-3-tert.pentylaminopropoxy) indole-2-carboxylate (Method b)

30.5 g of 4-hydroxyindole-2-carbonsäureäιhylestcr, 165 g of epichlorohydrin and 2 drops of piperidine are / 4 ^1: hours heated to boiling. The excess epichlorohydrin is distilled off under reduced pressure and 14 g of the remaining residue in 5.3 g

ίο tert.Pentylamine and 50 ml of dioxane added and heated to boiling for Vh hours. It is evaporated to dryness under reduced pressure and then the residue is shaken out between ethyl acetate and 1N tartaric acid solution. The combined tartaric extracts are carefully made alkaline with 10% sodium carbonate solution while cooling with ice and then extracted with methylene chloride. The methylene chloride phases are dried over magnesium sulfate and evaporated. Crystallization of the evaporation residue from ethyl acetate gives the compound mentioned in the title as a boat with a melting point of 135-137 °.

Example 5

4- (2-Hydroxy-3-isopropylaminopropoxy) -indoi-2-carboric acid methyl ester (Method a)

To a solution of 1.91 g of 4-hydroxy-indole-2-carboxylic acid methyl ester and 0.4 g of sodium hydroxide in 150 ml of methanol are added 4.8 g of 1- (N-benzylisopropylamino) -3-chloro-2propanol and heated to boiling for 20 hours. The solvent is evaporated off under reduced pressure and the triturated Residue several times with petroleum ether. 4- [3- (N-Benzylisopropylamino) -2-hydroxypropoxy] indole-2-carboxylic acid methyl ester is obtained, which is identical to the intermediate product prepared according to Example 2: mp 115-117 ° after crystallization from ethanol / ethyl acetate.

By debenzylation as described in Example 2, the compound mentioned in the title is obtained, whose N-Cyclohexylsulfamate crystallized from ethanol / ether in needles with a melting point of 110-113 °.

The starting material can be produced, for example, as follows:

A mixture of 18.4 g of epichlorohydrin and 29.8 g of N-benzylisopropylamine in 100 ml of benzene is heated refluxed for 24 hours, then evaporated the solvent and distilled the Residue in high vacuum; i- (N-Benzyiisopropylamino) -3-chloro-2-propanol is obtained from Sdp. 110-115 ° / 0.2 mm Hg.

Example 6

Ethyl 4- (2-hydroxy-3-isopropylaminopropoxy) indole-2-carboxylate (Method b)

The procedure is as described in Example 1, but epiiodohydrin is used instead of epichlorohydrin. The compound mentioned in the title is obtained, which is obtained with the product prepared according to Example 1 is identical (m.p. 149-151 ° from isopropanol).

Example 7

4- (2-Hydroxy-3-isopropylaminopropoxy) -indole-2-carboxylic acid methyl csicr (method a)

The procedure described in Example 2 is followed, but epifluorohydrin is used instead of epichlorohydrin. The compound mentioned in the title, which is identical to the product prepared according to Example 2, is obtained. Melting point 143-145 ^Ü after crystallization from ethyl acetate.

Example 8

Ethyl ethyl 4- (3-tert-butylamino-2-hydroxy propoxy) indole-2-carboxylic acid (Method a)

The procedure described in Example 3 is followed, but epibromohydrin is used instead of epichlorohydrin. The compound named in the title is obtained. which with the product prepared according to Example 3 is identical. The N-cyclohexylsulfamate of this compound crystallizes from ethanol / ether (m.p. 169-171 °).

Example 9

Ethyl 4- (2-hydroxy-3-tert.pentylaminopropoxy) indole-2-carboxylate (Method b)

The procedure described in Example 4 is followed, but epibromohydrin is used instead of epichlorohydrin. The compound mentioned in the title is obtained, which is obtained with the product prepared according to Example 4 is identical (m.p. 135-137 ° from ethyl acetate). 13th

Example 10

4- (2-Hydroxy-3-isopropylaminopropoxy) indole-2-carboxylic acid methyl ester (Method a)

The procedure described in Example 5 is followed, but epifluorohydrin is used instead of epichlorohydrin. The N-cyclohexylsulfamate of the compound mentioned in the title is obtained after crystallization Ethanol / ether (m.p. 110-113 °).

Example 11

4- (2-Hydroxy-3-isopropylaminopropoxy) indole-2-carboxylic acid methyl ester (Method a)

The procedure described in Example 5 is followed, but epiiodohydrin is used instead of epichlorohydrin. The N-cyclohexylsulfamate of the compound mentioned in the title is obtained after crystallization from ethanol / ether (M.p. 110-113 °).

example

2-hydroxy methyl-4- (2-hydroxy-3-isopropylaminopropoxy) indole (Method b)

The procedure is analogous to Example 1, starting from 4-hydroxy-2-hydroxymethylindole, under a nitrogen atmosphere and receives the compound mentioned in the title (m.p. 145-148 - from ethanol).

Used as a starting product 4-hydroxy-2-hydroxyineihylindol (SINP 112-114 ° -. From benzene / Essigester) is r · by debenzylation of 4-Bcn / 2-yloxy ..juroxyniethylindol with hydrogen in the presence of a 5% palladium catalyst on alumina. 4-Benzyloxy-2-hydroxymethylindole (m.p. 109-111 ° - from benzene) is prepared by reducing 4-benzyloxyindole-2-carboxylic acid with lithium aluminum hydride in boiling dioxane.

This reduction can also be carried out as follows:

To a boiling suspension of 534 g of 4-benzyloxyindole-2-carboxylic acid and 4 liters of abs. Benzene is added dropwise with stirring and under a nitrogen atmosphere, 1200 g of a 70% solution of sodium dihydrobis (2-methoxyethoxy) aluminate in benzene and then simmered for 1 hour.

The mixture is then decomposed at 15-25 ° by dropwise addition of 3 liters of 2N hydrochloric acid, filtered clear and separates the organic phase. The latter is washed twice with 800 ml of 2N sodium hydroxide solution each time and then dried evaporated over magnesium sulfate and under reduced pressure.

Example 14

2-hydroxymethyl-4- (2-hydroxy-3-isopropylaminopropoxy) -iiidol Method b)

The procedure described in Example 13 is followed, but epibromohydrin is used instead of epichlorohydrin.

The product is identical to the compound obtained according to Example 13.

Example 15

4- (2-hydroxy-3-isopropylaminopropoxy) -2-hydroxymethylindole (Method b)

The procedure is analogous to Example 4, starting from 4-hydroxy-2-hydroxymethylindole and isopropylamine and receives the compound mentioned in the title (melting point of 145-148 ° - from ethanol).

Example 16

4- (3-tert-butylamino-2-hydroxypropoxy) -2-hydroxymeinyliiidül (Method b)

The procedure is analogous to Example 13, starting from 4-hydroxy-2-hydroxymethylindole and the im Title compound as coarse crystals (melting point 124-126 °).

Example 12

4- (2-Hydroxy-3-isopropylaminopropoxy) indole-2-carboxylic acid methyl ester (Method a)

The procedure described in Example 5 is followed, but epibromohydrin is used instead of epichlorohydrin. The N-cyclohexylsulfamate of the compound mentioned in the title is obtained after crystallization Ethanol / ether (m.p. 110-113 °).

Example 17

4- (3-tert-butylamino-2-hydroxypropoxy) -2-hydroxymethylindole (Method b)

The procedure is analogous to Example 16, starting with 4-hydroxy-2-hydroxymethylindole and using of epifluorohydrin instead of epichlorohydrin. The compound mentioned in the title is obtained as a coarse crystallizate (M.p. 124-126).

Example 18

4- (3-5ec.Butylamino-2-hydroxypropoxy) -2-hydroxymethy! Indole (method b)

The procedure is analogous to Example 13, starting from sec.Butylamine instead of isopropylamine and the im Compound named in the title (m.p. 110-111 ° from Ethyl acetate / ether).

Example 19

4- (3-sec-butylamino-2-hydroxypropoxy) -2-hydroxymethylindole (Method b)

The procedure described in Example 18 is followed, but epibromohydrin is used instead of epichlorohydrin. The compound mentioned in the title, which was prepared with that according to Example 18, is obtained Product is identical (m.p. 110-111 ° from ethyl acetate / Ether).

Example 20

4- (3-sec-butylamino-2-hydroxypropoxy) -2-hydroxymethylindole (Method b)

The procedure described in Example 18 is followed, but epiodohydrin is used instead of epichlorohydrin. The compound mentioned in the title, which was prepared with that prepared according to Example 18, is obtained Product is identical (m.p. 110-111 ° from ethyl acetate / Ether).

Example 21

4- (3-sec-butylamino-2-hydroxypropoxy) -2-hydroxymethylindole (Method b)

The procedure described in Example 18 is followed, but epifluorohydrin is used instead of epichlorohydrin. The compound mentioned in the title, which was prepared with that according to Example 18, is obtained Product is identical (m.p. 110-111 ° from ethyl acetate / ether).

Example 22

4- (2-Hydroxy-3-tert-pentyIaminopropoxy) -2-hydroxymethylindole (Method b)

The procedure is analogous to that given for Example 13 Regulation, with tert-pentylamine instead of isopropylamine used. The hydrogen maleate of the compound mentioned in the title crystallizes from ethanol / acetone / ethyl acetate in crystals with a melting point of 123 ° -129 °.

Example 23

4- [2-Hydroxy-3- (3-pentylamino) propoxy] -2-hydroxymethylindole (Method b)

The procedure is analogous to that given for Example 13 Regulation, using 3-pentylamine instead of isopropylamine used. The compound mentioned in the title crystallizes from ethyl acetate. M.p. 126-127 °.

Example 24

4- (2-Hydroxy-3-tert.pentylaniinopropoxy) -2-hydroxymethylindole (Method b)

Proceed as described in Example 22, but uses epibromohydrin instead of epichlorohydrin. You get the connection mentioned in the Tilel,

which is identical to the product prepared according to Example 22 (melting point 123-129 ° from ethanol / acetone / ethyl acetate).

Example 25

4- [2-Hydroxy-3- (3-pentylamino) propoxy] -2-hydroxymethylindole (Method b)

Proceed as described in Example 23,

ίο uses epifluorohydrin instead of epichlorohydrin. The compound mentioned in the title is obtained, which is prepared with that according to Example 23 Product is identical (m.p. 126-127 ° from ethyl acetate).

Example 26

4- (2-hydroxy-3-isopropylaminopropoxy) -2-hydroxymethylindole (Method a)

The procedure is analogous to Example 5, starting from 4-hydroxy-2-hydroxymethylindole and the im Title compound with a melting point of 145-148 ° (from ethyl acetate).

The production of the 1 - (N-benzylisopropylamino) -3-chloro-2-propanol required as a starting product is as described under Example 5, carried out.

Example 27

4- (2-hydroxy-3-isopropylaminopropoxy) -2-hydroxymethylindole (Method a)

The procedure is analogous to that given for Example 26, but instead of I- (N-benzylisopropylamino) -3-chloro-2-propanol 1 - (N-Benzylisopropylamino) -3-bromo-2-propanol is used. You get the im Compound named title which is identical to the product prepared according to Example 26 (Snip. 145-148 ° from ethyl acetate).

Example 28

4- (2-Hydroxy-3-isopropylaminopropoxy) -2-hydroxymethylindo! (Method a)

The procedure is analogous to that given for Example 26, with I- (N-benzylisopropylamino) -3-chloro-2-propanol instead 1- (N-benzylisopropy! Amino) -3-fluoro-2-propanol is used. You get the im The title compound which is identical to the product prepared according to Example 26 (m.p. 145-148 ° from ethyl acetate).

Example 29

4- (2-hydroxy-3-isopropylaminopropoxy) -2-hydroxymethylindole (Method a)

The procedure given for Example 26 is repeated, instead of 1- (N-benzylisopropylamino) -3-chloro-2-propanol 1- (N-Benzylisopropylaniino) -3-iodo-2-propanol is used. You get that in the title named compound, which is identical to the product prepared according to Example 26 (melting point 145-148 ° from ethyl acetate).

Example 30

4- (2-Hydroxy-3-isopropylaminopropoxy) -2-hydroxymeth> lindole (Method c)

To a boiling suspension of 7.f> g lithium aluminum hydride in 200 ml abs. Tetrahydrofuran drips

a solution of 32 g is obtained for 15 minutes while stirring and under a nitrogen atmosphere Ethyl 4- {2-hydroxy-3-isopropylaminopropoxy) indole-2-carboxylate in 250 ml ..bs. Tetrahydrofuran and stirred for a further 2 hours. Then you cool down 40 ° and drop in 20 ml of water. The resulting precipitate is filtered off, well with tetrahydrofuran washed out and the organic solution dried over sodium sulfate. The residue from evaporation is recrystallized from 480 ml of acetonitrile and gives the compound mentioned in the title (melting point 145-147 °).

The ethyl 4- (2-hydroxy-3-isopropylaminopropoxy) indole-2-carboxylate required as the starting product is as described in Example 1, prepared.

Example 31

4- (2-Hydroxy-3-isopropylaminopropoxy) indole-2-carboxylic acid isopropyl ester (Method a)

50.6 g of 4-hydroxyindole-2-carboxylic acid isopropyl estersΓ, 215 ml of epichlorohydrin and 5 drops of piperidine will be added heated to boiling under reflux for 8 hours. Then it is evaporated under reduced Pressure the excess epichlorohydrin. 21 g of the crude epoxide thus obtained are mixed with 13 g of benzylisopropylamine taken up in '.0OmI dioxane and heated to boiling under reflux for 8 hours. Man evaporated the solvent and excess benzylisopropylamine in vacuo and isolated from the The residue in the usual way by shaking between ethyl acetate and 1 N tartaric acid solution basic components. 22 g of the 4- (3-benzylisopropylamino-2-hydroxypropoxy) indole-2-carboxylic acid obtained Reisopropylesters are mixed with 10 g of palladium catalyst (5% Pd on carbon) in 400 ml of isopropanol Shake hydrogen until hydrogen uptake has ceased. After removing the catalyst it is evaporated to dryness under reduced pressure and the title compound is crystallized from ethyl acetate / petroleum ether; (mp. 167 to 168 °, Nadein).

Example 32

4- (3-tert-Butylamino-2-hydroxypropoxy) -indole-2-carboxylic acid isopropyl ester (Method a)

The procedure is analogous to that given for Example 31

Regulation, whereby instead of benzylisopropyllain Benzyl-tert-butylamine is used. The one mentioned in the title

Compound crystallizes from ethyl acetate / ether in crystals from m.p. 137 to 140 °.

Example of a pharmaceutical preparation: tablets

Latvians

Ethyl 4- (2-hydroxy-3-isopropylaminopropoxy) indole-2-carboxylate 0.0200 g

Magnesium stearate 0.0010 g

Polyvinyl pyrrolidone

Talk

Cornstarch

Milk sugar

Dimethyl silicone oil

Polyethylene glycol 6000

For one tablet of

0.0040 g 0.0080 g 0.0100 g 0.1535 g 0.0005 g 0.0030 g

0.2000 g

Instead of 4- (2-hydroxy-3-isopropylaminopropoxy) -indole-

2-carboxylic acid ethyl ester can, for. B. also 4- (2-hydroxy-3-isopropylaminopropoxy) -2-hydroxymethylindole as

active substance can be used, the same proportions can be used.

Claims (1)

Patent claims: 1. 4- (2-Hydroxy-3-aminopropoxy) indole derivatives of the general formula! OH wherein R _{2 has the} above meaning and Y represents a halogen atom, or a mixture of the compounds of the general formulas Ha and Hb with an amine of the general formula »III, H ₂ NR ₁ (DT)